part 3: obstacles to developing targeted cancer...
TRANSCRIPT
Part 3: Obstacles to Developing Targeted Cancer Therapies
Adrianna San Roman Leah Liu
Clare Malone
If targeted therapies are so great, why can’t we treat all
cancers?
Obstacles
• IdenFfying targets
• Finding medicines for targets
• Moving into the clinic
• Cancer resistance
Obstacle 1: Targeted therapies require targets!
Wikimedia
How do you idenFfy a target? Discover differences between normal cells and cancer cells: • DNA mutaFons • Protein levels
Problem: Most cancer cells have DNA that looks like someone exploded their DNA and then put it
back together randomly Michale Strock
Driver vs. Passenger MutaFons
“Driver” is causing the cancer
“Passenger” is a mutaFon that happens along the way to becoming cancer, but isn’t causing the cancer
Which mutaFons are “drivers”?
geograph.org.uk
SoluFon: Look for common mutaFons in many tumor samples
However, rare but important “driver” mutaFons will be overlooked, and are very difficult to idenFfy
Sample 1 Sample 2 Sample 3 Sample 4
Not all driver mutaFons are good targets
B D C A
Normal Cancer
Obstacle 2: HiYng the Target
Which protein has a targeted therapy?
Mutated in 20‐25% of all human cancers
Importance in human cancer discovered in
1982
Mutated in 7% of all human cancers
Importance in human cancer discovered in
2002
✔
A
B B‐raf
Ras
Cell Growth Example – Ras Pathway
B‐raf
Abnormal cell
growth and
division
Ras Mek
Cancer Cell
Signal Receptor Pathway Component
Pathway Component
Output Pathway Component
PLX4032 Growth signal Cell
growth and
division
p53
Tumor suppressors: How do you “target” something that is not there?
Fixing mistakes in DNA
Control of Cell Division
Control of Cell Death
So far we’ve learned…
1. It can take years of research to idenFfy promising targets
2. It can be difficult or impossible to find medicines that alter promising targets
Obstacle 3: Moving from the lab to the clinic does not always work
Photo by Umberto Salvagnin hhp://www.flickr.com/photos/kaibara/3075268200/
How many potenFal medicines make it into clinical trials?
A.) 1 in 100 B.) 1 in 1000 C.) 1 in 10,000
Why don’t they make it to clinical trial?
• Cannot be effecFvely delivered to paFent (oral, IV etc)
• Not stable enough for use in the clinic
• Not specific for target • Toxic to normal cells
Most potenFal medicines fail in clinical trials
0 10 20 30 40 50 60 70 80 90 100
All indicaFons
Ovarian Cancer
Breast Cancer
Prostate Cancer
Colorectal Cancer
Non‐small cell lung cancer
Med
icines app
roved a9
er trials
7% 4% 3% 2% 9% 8%
BioMedTracker BIO study 2011 Insidebiola.com
Why do medicines fail?
• Can’t give enough medicine to people • Medicine does not do what we thought it
would • Medicine hits target, but target is less
important than we thought
2.) Medicine has too many side effects
1.) Medicine is not effecFve
• “Off‐target” effects • HiYng target not safe
TherapeuFc window
Dose
Bene
fit
Targeted therapies might have beher luck
• More is understood about the biology before trials are started (beher efficacy)
PLX4032’s end‐stage clinical trial is the shortest on record!
B‐raf
Cancer growth
• Risk of serious side‐effects is expected to be lower (safer)
This means a wider therapeuFc window, so it is easier to achieve effecFve doses safely!
Obstacle 4: Cancer is always changing
How does cancer fight back?
Medicine Resistance
Resistance to PLX4032
Before therapy Aoer therapy Average relapse: 7 months
?
Flaherty et al. N Engl J Med 2010; 363:809‐819.
Mechanism of Resistance #1
Cancer cell growth and division
Cancer cell growth and division
New mutaFon
Secondary mutaFon in the target protein
Ras Pathway
B‐raf Ras
Growth signal
Mek
Cell
Signal Receptor Pathway Component
Pathway Component
Output Pathway Component
Cell growth and
division
Mechanism of Resistance #2
Cancer cell growth and division
B‐raf
Mek
MutaFon in a downstream protein
Mechanism of Resistance #3
Cancer cell growth and division
B‐raf
Mek
MutaFon bypasses target protein
Cancer resistance to targeted therapies
• Resistance is a common problem in targeted therapies
• Some common mechanisms include: Second mutaFon in the target protein MutaFon in a protein downstream of the target MutaFon that bypasses the target protein
• CombinaFon therapies may help combat resistance
What we learned tonight:
Adrianna: Principles of cancer • How cancer cells are different from normal cells • Why is not one disease
Leah: Cancer therapeuFcs • Chemotherapy and radiaFon • Targeted therapies
Clare: Obstacles to developing cancer therapies • IdenFfying and hiYng targets • TranslaFng discoveries to the clinic • Cancer resistance to therapy
Why haven’t we won the war on cancer yet?
Because it is not one war, so it requires more than one soluFon.
We have made progress in some major bahles!
Cancer Type 1975 5‐year Survival Rate 2011 5‐year Survival Rate
PromyelocyFc Leukemia 35% 98%
Childhood Leukemias 30% 80%
Chronic Myelogenous Leukemia
23.1% 89%
Fausel, 2007 Druker NEJM 2006 SEER Cancer StaFsFcs Review. 1975‐2008
What does the future of cancer therapy look like?
Near Future: • More targeted therapies
• Second‐ and third‐line therapies to combat resistance
Distant Future: • CombinaFon of medicine specific for paFent
• Manageable chronic disease
Thank you! SITN would like to acknowledge the following
organiza;ons for their generous support. Harvard Medical School
Office of CommunicaFons and External RelaFons Division of Medical Sciences
The Harvard Graduate School of Arts and Sciences (GSAS)
The Harvard Graduate Student Council (GSC)
The Harvard Biomedical Graduate Students OrganizaPon (BGSO)
The Harvard/MIT COOP
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